The ability to store and retrieve sequentially related information is arguably the foundation of intelligent behavior. It allows us to predict the outcomes of sensory situations, to achieve goals by generating sequences of motor actions, to 'mentally' explore the possible outcomes of different navigational or motor choices, and ultimately to communicate through complex verbal sequences generated by flexibly chaining simpler elemental sequences learned in childhood. Sleep extracts invariant features from the learned information, leading to the generation of explicit knowledge and insight. Despite remarkable progress, including work by PI and co-PI of this project, many critical questions remain about role of sleep in memory and learning. Here we propose to address these questions through the development of computational models that are probed and validated through in vivo experiments in mice. We will explore the hippocampal (HC) and neocortical (NC) mechanisms underlying how sequences are acquired and subsequently consolidated through off-line replay during Slow Wave Sleep (SWS) in a manner that minimizes interference between overlapping and/or reversed sequences and how NC may chain sequence fragments together. We combine computer modelling (Bazhenov) of spiking neural networks that mimic awake and SWS brain dynamics, including NC slow oscillations and HC Sharp Wave Ripples (SWR), with high density neural ensemble recordings (McNaughton) in mice, in a controlled behavioral setting including sequence learning and subsequent, chemogenetically induced SWS, which makes it possible to observe how learned sequence representations in NC evolve spontaneously over prolonged periods of SWS. The PIs have been collaborating on and discussing this topic for the past several years, resulting in specific hypotheses that can be explored in real brains. The project outcome will provide a better understanding of how knowledge is extracted from experience, what brain circuits are involved and how brain dynamics are shaped by the development of a rich internal model of the world, including the ability to predict the outcomes of current situations and one's own actions in that context. RELEVANCE (See instructions): The ability to store and retrieve sequentially related information is the foundation of intelligent behavior and brain executive function. Deficits in this ability, resulting from disruption of brain circuits, are seen in depression, schizophrenia and PTSD. Better understanding of the mechanisms and brain dynamics underlying the acquisition, consolidation and retrieval of sequential information will lead to interventions to improve cognitive performance, memory and learning in healthy subjects and patients with mental illness.